ErbB2/neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells

Rebecca S. Muraoka, Anne E.G. Lenferink, Brian Law, Elizabeth Hamilton, Dana M. Brantley, L. Renee Roebuck, Carlos L. Arteaga

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Abstract

ErbB2/Neu destabilizes the cyclin-dependent kinase (Cdk) inhibitor p27 and increases expression of cyclin D1. Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation. Overexpression of ErbB2 or cyclin D1 in p27+/- primary murine mammary epithelial cells resulted in increased proliferation, cyclin D1 nuclear localization, and colony formation in soft agar compared to those in p27+/+ cells. In contrast, ErbB2- or cyclin D1-overexpressing p27-/- cells displayed reduced proliferation, anchorage-independent growth, Cdk4 activity, cyclin D1 expression, and cyclin D1 nuclear localization compared to wild-type cells. A cyclin D1 mutation in its nuclear export sequence (T286A) partially rescued nuclear localization of cyclin D1 in p27-/- cells but did not increase proliferation or Cdk4 kinase activity. Overexpression of E2F1, however, increased proliferation to the same degree in p27+/+, p27+/-, and p27-/- cells. Mammary glands from MMTV (mouse mammary tumor virus)-neu/p27+/- mice exhibited alveolar hyperplasia, enhanced proliferation, decreased apoptosis, and accelerated tumor formation compared to MMTV-neu/p27+/+ glands. However, MMTV-neu/p27-/- glands showed decreased proliferation, cyclin D1 expression, and Cdk4 activity, as well as markedly prolonged tumor latency, compared to MMTV-neu/p27+/+ glands. These results suggest that p27+/- mammary epithelium may be more susceptible to oncogene-induced tumorigenesis, whereas p27-null glands, due to severely impaired cyclin D1/Cdk4 function, are more resistant to transformation.

Original languageEnglish (US)
Pages (from-to)2204-2219
Number of pages16
JournalMolecular and Cellular Biology
Volume22
Issue number7
DOIs
StatePublished - Mar 25 2002

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Null Lymphocytes
Cyclin D1
Breast
Epithelial Cells
Mouse mammary tumor virus
Cyclin-Dependent Kinase Inhibitor p27
Cell Nucleus Active Transport
Human Mammary Glands
Oncogenes
Agar
Hyperplasia
Neoplasms
Carcinogenesis
Phosphotransferases
Epithelium
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

ErbB2/neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. / Muraoka, Rebecca S.; Lenferink, Anne E.G.; Law, Brian; Hamilton, Elizabeth; Brantley, Dana M.; Roebuck, L. Renee; Arteaga, Carlos L.

In: Molecular and Cellular Biology, Vol. 22, No. 7, 25.03.2002, p. 2204-2219.

Research output: Contribution to journalArticle

Muraoka, Rebecca S. ; Lenferink, Anne E.G. ; Law, Brian ; Hamilton, Elizabeth ; Brantley, Dana M. ; Roebuck, L. Renee ; Arteaga, Carlos L. / ErbB2/neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 7. pp. 2204-2219.
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AU - Lenferink, Anne E.G.

AU - Law, Brian

AU - Hamilton, Elizabeth

AU - Brantley, Dana M.

AU - Roebuck, L. Renee

AU - Arteaga, Carlos L.

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AB - ErbB2/Neu destabilizes the cyclin-dependent kinase (Cdk) inhibitor p27 and increases expression of cyclin D1. Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation. Overexpression of ErbB2 or cyclin D1 in p27+/- primary murine mammary epithelial cells resulted in increased proliferation, cyclin D1 nuclear localization, and colony formation in soft agar compared to those in p27+/+ cells. In contrast, ErbB2- or cyclin D1-overexpressing p27-/- cells displayed reduced proliferation, anchorage-independent growth, Cdk4 activity, cyclin D1 expression, and cyclin D1 nuclear localization compared to wild-type cells. A cyclin D1 mutation in its nuclear export sequence (T286A) partially rescued nuclear localization of cyclin D1 in p27-/- cells but did not increase proliferation or Cdk4 kinase activity. Overexpression of E2F1, however, increased proliferation to the same degree in p27+/+, p27+/-, and p27-/- cells. Mammary glands from MMTV (mouse mammary tumor virus)-neu/p27+/- mice exhibited alveolar hyperplasia, enhanced proliferation, decreased apoptosis, and accelerated tumor formation compared to MMTV-neu/p27+/+ glands. However, MMTV-neu/p27-/- glands showed decreased proliferation, cyclin D1 expression, and Cdk4 activity, as well as markedly prolonged tumor latency, compared to MMTV-neu/p27+/+ glands. These results suggest that p27+/- mammary epithelium may be more susceptible to oncogene-induced tumorigenesis, whereas p27-null glands, due to severely impaired cyclin D1/Cdk4 function, are more resistant to transformation.

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